Restraining SRD5A1 combined with BRD4 inhibitor delaying prostate cancer progression by decreasing AR expression

With increasing life expectancy, prostate cancer (PCa) has exhibited rising incidence and mortality rates. Although therapies such as androgen deprivation therapy (ADT) effectively extend patient survival, the development of drug resistance remains a major obstacle. Previous studies identified a key enzyme in the androgen metabolic pathway as essential to PCa progression, regulated by the epigenetic reader BRD4. Bioinformatic analysis revealed that SRD5A1, a critical enzyme in androgen metabolism, is downregulated by the BRD4 inhibitor JQ1. This finding was validated using I-BET151, another BRD4 inhibitor, which also suppressed SRD5A1 expression in PCa cell lines. Furthermore, treatment with dutasteride (Duta), an SRD5A family inhibitor, significantly reduced both cell proliferation and invasion. Mechanistic investigations demonstrated that SRD5A1 promotes androgen receptor (AR) activity by elevating intracellular dihydrotestosterone (DHT) levels, thereby enhancing AR expression and facilitating tumorigenesis. Notably, both BRD4 and SRD5A1 were shown to modulate AR expression in PCa cells. Co-administration of BRD4 and SRD5A1 inhibitors yielded a more pronounced suppression of AR expression. These findings highlight the pivotal role of SRD5A1 in PCa progression and suggest that combinatorial inhibition of BRD4 and SRD5A1 may provide a more effective strategy for attenuating AR expression and halting disease development.